- Synthesis and Hypoglycemic Activity of Aryl(Hetaryl)Propenoic Cyanopyrrolidine Amides
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Abstract: A series of amides based on (2S)-cyanopyrrolidine and α, β-unsaturated aryl- and hetarylcarboxylic acids have been synthesized. The dependence of the hypoglycemic activity of compounds on the structure of the aromatic fragment has been studied in the oral glucose tolerance test in mice. Amides based on (E)-3-phenylprop-2-enoic and (E)-3-(4-methoxyphenyl)prop-2-enoic acids and (2S)-cyanopyrrolidine have been shown to significantly reduce blood glucose levels in mice. The observed hypoglycemic effect at a dose of 10 mg/kg is comparable to the effect of hypoglycemic drug vildagliptin.
- Kuranov,Blokhin,Borisov,Khvostov,Luzina,Salakhutdinov
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p. 374 - 380
(2019/10/28)
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- Dual-targeting Rutaecarpine-NO donor hybrids as novel anti-hypertensive agents by promoting release of CGRP
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CGRP, known as the most potent vasodilator substance, plays an important role in hypertension initiation and development. TRPV1 and TRPA1 are critical in promoting the synthesis and release of CGRP, thereby regulating the cardiovascular tone. Rutaecarpine exhibits potent vasodilator and hypertensive effects by stimulating CGRP synthesis and release via activation of TRPV1. And NO has been shown to react with H2S in vivo to form HNO, thereby activating HNO-TRPA1-CGRP pathway. Inspired by combination therapy, 11 rutaecarpine-furoxan hybrids were designed, synthesized and evaluated. The results demonstrated that most hybrids exerted comparable or improved vasodilator activities. Among which, 13a is the most potent both ex vivo (EC50 = 13.1 nM) and in vivo. Mechanistic studies revealed that the vasodilator and anti-hypertensive effects of the hybrids might involve the promotion of CGRP release via dual activation of TRPV1 and TRPA1. This work suggests that dual-targeted hybrids might be an effective and promising approach to discover and develop novel anti-hypertensive drugs.
- Ma, Jinjin,Chen, Lan,Fan, Jinbao,Cao, Wei,Zeng, Guangyao,Wang, Yajing,Li, Yuanjian,Zhou, Yingjun,Deng, Xu
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supporting information
p. 146 - 153
(2019/02/27)
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- A METHOD FOR THE SITE-SPECIFIC ENZYMATIC LABELLING OF NUCLEIC ACIDS IN VITRO BY INCORPORATION OF UNNATURAL NUCLEOTIDES
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Provided herein are analogs of unnatural nucleotides bearing predominantly hydrophobic nucleobase analogs that form unnatural base pairs during DNA polymerase- mediated replication of DNA or RNA polymerase-mediated transcription of RNA. In this manner, the unnatural nucleobases can be introduced in a site-specific way into oligonucleotides (single or double stranded DNA or RNA), where they can provide for site-specific cleavage, or can provide a reactive linker than can undergo functionalization with a cargo -bearing reagent by means of reaction with a primary amino group or by means of click chemistry with an alkyne group of the unnatural nucleobase linker.
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Paragraph 00176
(2015/02/25)
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- FUSED THIOPHENE AND THIAZOLE DERIVATIVES AS ROR GAMMA MODULATORS
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The present invention provides fused thiophene and thiazole derivatives of formula (I), which may be therapeutically useful, more particularly as RORγ modulators; in which R1, R2, R3, R4, R5, R6, R7, X1, X2, L, m, n and ring A have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in disease(s) or disorder(s) where there is an advantage in modulating RORγ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the fused thiophene and thiazole derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 80; 81
(2015/07/16)
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- Synthesis of 2-(hetero)aryl-5-(trimethylsilylethynyl)oxazoles from (hetero)arylacrylic acids
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A three-step method for the synthesis of 2-(hetero)aryl-5-(trimethylsilylethynyl)oxazoles is described. Easily accessible bis(trimethylsilyl)acetylene and acrylic acid derivatives are used as starting materials for the preparation of mono- and disubstituted 5-(trimethylsilyl)pent-1-en-4-yn-3-ones. Oxidative phthalimidoaziridination of these enynones provides the key 2-acyl-1-phthalimidoaziridines that are further utilized in the thermal expansion of the three-membered ring to furnish the target functionalizable oxazoles.
- Pankova, Alena S.,Stukalov, Alexander Yu.,Kuznetsov, Mikhail A.
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supporting information
p. 1826 - 1829
(2015/04/27)
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- Natural-like replication of an unnatural base pair for the expansion of the genetic alphabet and biotechnology applications
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We synthesized a panel of unnatural base pairs whose pairing depends on hydrophobic and packing forces and identify dTPT3-dNaM, which is PCR amplified with a natural base pair-like efficiency and fidelity. In addition, the dTPT3 scaffold is uniquely tolerant of attaching a propargyl amine linker, resulting in the dTPT3PA-dNaM pair, which is amplified only slightly less well. The identification of dTPT3 represents significant progress toward developing an unnatural base pair for the in vivo expansion of an organism's genetic alphabet and for a variety of in vitro biotechnology applications where it is used to site-specifically label amplified DNA, and it also demonstrates for the first time that hydrophobic and packing forces are sufficient to mediate natural-like replication.
- Li, Lingjun,Degardin, Melissa,Lavergne, Thomas,Malyshev, Denis A.,Dhami, Kirandeep,Ordoukhanian, Phillip,Romesberg, Floyd E.
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supporting information
p. 826 - 829
(2014/02/14)
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- N-Heterocyclic carbene-Pd(II) complex derived from proline for the Mizoroki-Heck reaction in water
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N-Heterocyclic carbene-Pd(II) complex 1 derived from proline was found to be an efficient catalyst in the Mizoroki-Heck reaction of aryl bromides and iodides performed in water. The reactions can tolerate various functional groups in the substrates and all gave the corresponding coupling products in good to high yields.
- Tang, Yi-Qiang,Chu, Chun-Yan,Zhu, Lei,Qian, Bin,Shao, Li-Xiong
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experimental part
p. 9479 - 9483
(2011/12/15)
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- Design and synthesis of piperazinylpyridine derivatives as novel 5-HT 1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS)
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We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT 1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piper-azine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.
- Asagarasu, Akira,Matsui, Teruaki,Hayashi, Hiroyuki,Tamaoki, Satoru,Yamauchi, Yukinao,Sato, Michitaka
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experimental part
p. 34 - 42
(2009/07/18)
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- Acylaminothiazole derivatives, their preparation and their therapeutic use
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Compound corresponding to the general formula (I): in which, X represents an oxygen or sulphur atom; R1 represents a C1-10 alkyl group optionally substituted, a C3-7 cycloalkyl, thienyl, pyridinyl or pyrimidinyl group; the thienyl groups being optionally substituted; the phenyl group being optionally substituted; R2 represents a C1-6 alkyl group optionally substituted, a C3-7 cycloalkyl, piperidinyl, phenyl or pyridinyl group; the C3-7 cycloalkyl and piperidinyl groups being optionally substituted; the phenyl and pyridinyl groups being optionally substituted; R3 represents a hydrogen atom or a C1-6 alkyl group optionally substituted with a C3-7 cycloalkyl group; R4 represents a hydrogen atom or a C1-6 alkyl group; R5 and R5′ represent, independently of each other, a hydrogen or halogen atom, a hydroxyl or C1-3 alkyl group; or R5 and R5′ form together an oxo or oxime group such as: where R7 represents a hydrogen atom or a C1-3 alkyl; n represents an integer ranging from 0 to 3; and R6 represents, independently of each other when n=2 or 3, a hydrogen or halogen atom, a hydroxyl, C1-3 alkyl, C1-3 alkoxy, C1-3 fluoroalkyl or C1-3 fluoroalkoxy group; in the form of a base, of an addition salt with an acid, of a hydrate or of a solvate. therapeutic application.
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Page/Page column 10
(2008/06/13)
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- The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase from parsley
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Acrylic acids and alanines substituted with heteroaryl groups at the β-position were synthesized and spectroscopically characterized (UV, HRMS, 1H NMR, and 13C NMR spectroscopy). The heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl and contained the alanyl side chains either at the 2- or 3-positions. While the former are good substrates for phenylalanine ammonia lyase (PAL), the latter compounds are inhibitors. Exceptions are thiophen-3-yl-alanine, a moderate substrate and furan-3-yl-alanine, which is inert. Possible reasons for these exceptions are discussed. Starting from racemic het eroaryl-2-alanines their D-enantiomers were prepared by using a stereodestructive procedure. From the heteroaryl-2- acrylates, the L-enantiomers of the heteroaryl-2-alanines were prepared at high ammonia concentration. These results can be best explained by a Friedel - Crafts-type electrophilic attack at the aromatic part of the substrates as the initial step of the PAL reaction.
- Paizs, Csaba,Katona, Adrian,Retey, Janos
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p. 2739 - 2744
(2008/02/03)
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- Preparation of vinylphenols from 2- and 4-hydroxybenzaldehydes
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A straightforward, high-yielding procedure has been developed for the manufacture of substituted vinylphenols from 2- and 4-hydroxybenzaldehydes utilising classical Knoevenagel condensation reaction conditions.
- Simpson, Carol J.,Fitzhenry, Matthew J.,Stamford, N. Patrick J.
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p. 6893 - 6896
(2007/10/03)
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- Synthesis, photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones.
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The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.
- DoganKoruznjak, Jasna,Slade, Neda,Zamola, Branimir,Pavelic, Kresimir,Karminski-Zamola, Grace
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p. 656 - 660
(2007/10/03)
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- Two-carbon homologation of aldehydes via silyl ketene acetals. 2. Study of the stereochemical control in the formation of (E)-alkenoic acids
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The condensation of C,O,O-tris(trimethylsilyl)ketene acetal 1 with aldehydes 2 in the presence of catalytic amounts of mercuric iodide at room temperature affords syn and anti β-trimethylsiloxy α-trimethylsilyl alkanoic acid silyl esters 3 in good yields. These new compounds gave, under acidic or basic conditions, E and (or) Z enoic acids 4. The paths for the formation of these alkenoic acids are discussed.
- Bellassoued,Mouelhi,Lensen
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p. 5054 - 5057
(2007/10/03)
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- KOH-promoted reaction of C,O,O-tris(trimethylsilyl) ketene acetal with aldehydes: Practical and easy access to (E)-α,β-ethylenic carboxylic acids
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The use of a catalytic amount of KOH has been found to be very efficient in promoting reaction of silylketene acetal 1 with aldehydes 2 to afford the corresponding (E)-α,β-ethylenic carboxylic acids 3 under very mild conditions.
- Lensen,Mouelhi,Bellassoued
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p. 1007 - 1011
(2007/10/03)
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- The Thienopyridine and Furopyridine Rings: New Pharmacophores with Potential Antipsychotic Activity
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Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furopyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings.Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response.In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furopyridine derivatives,the interaction of these molecules with the dopamine D2 receptor was weak.Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10.Despite the similarity these molecules share in their behavioral indices of antipsychotic acivity, it is likely that the thieno- and furopyridine rings employ different mechanisms to achieve this convergence of biological effects.
- New, James S.,Christopher, William L.,Yevich, Joseph P.,Butler, Rhett,Schlemmer, R. Francis,et al.
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p. 1147 - 1156
(2007/10/02)
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